Cervical cancer (CC), the second most prevalent cancer in women and the fifth cause of death by cancer among women worldwide is a considerable public health problem[1]. Around 470,000 new cases of cervical cancer are detected annually, mostly in developing nations, of which approximately half will die [2].
Cervical cancer is a cellular alteration that originates in the epithelium of the cervix and is initially apparent through slow and progressively evolving precursor lesions that can occur in various stages of cervical intraepithelial neoplasia (CIN), grouped into low and high-grade squamous intraepithelial lesions (LSIL and HSIL respectively). These lesions could evolve into cancer in situ (circumscribed to the epithelial surface) and/or invasive cancer once they have crossed over to the basal membrane of the epithelium [3]. The alteration in cell cycle control mediated by human papilloma virus (HPV) oncoproteins is the main molecular mechanism of action in cervical cancer [4-6]. HPV infection is very common and is present almost in 80% of women with an active sexual life [7]. The most frequently involved HPV genotype in these lesions is HPV 16, which can be observed in LSIL, HSIL and cancer, as well as in normal cytology [8-12]. Although oncogenic HPV is necessary for the transformation of cervical-epithelial cells, it is not a sufficient cause, and a variety of cofactors and molecular events influence whether cervical cancer will develop[13].
While cytological screening and HPV infection tests has substantially reduced cervical cancer incidence and mortality where it has been successfully implemented, it is limited by low single-test sensitivity and poor reproducibility for equivocal and minor abnormalities [14, 15].
Biomarkers that identify key molecular events involved in the initiation and progression of cervical cancer, regardless of etiologic co-factors, may prove to be useful for screening, diagnostic and clinical management purposes in both resource rich and developing countries. Epigenomic biomarkers may prove to be useful early detection, diagnostic and progression markers for cervical carcinoma[16]. DNA hypermethylation, the best understood epigenomic biomarker in cancer research, leads to changes in gene expression which accumulate during oncogenic progression and are potentially reversible [17]. Gene-specific DNA hypermethylation is an effective transcription silencing mechanism, which is more frequent than the gene inactivation produced by mutations or other genetic changes seen in cancer [18].
Studies on animals and humans have confirmed that promoter hypermethylation is also often present in the precursor lesions of a variety of cancers [17]. As a result, these changes could be used as diagnostic biomarkers for cervical neoplasia, either alone or in combination with cytology and HPV tests.
There is a continuing need in the art for means of diagnosing, characterizing, and monitoring cervical cancers.